What is apalutamide?
Apalutamide is an oral second-generation, nonsteroidal androgen receptor inhibitor. Apalutamide selectively binds to the androgen receptor at 5-fold greater affinity than bicalutamide on select cell lines.
How does apalutamide work?
Apalutamide binds directly to the ligand-binding site of androgen receptors and results in inhibition of androgen receptor nuclear translocation, DNA binding, and prevents androgen receptor-mediated transcription. Apalutamide results in decreased tumor cell proliferation and increased apoptosis and ultimately leads to decreased tumor volume.
What is this approved for?
Apalutamide is approved for patients with non-metastatic castration-resistant prostate cancer (NM-CRPC). Apalutamide is to be given in combination with a gonadotropin-releasing hormone analog or patients should have had a bilateral orchiectomy (androgen deprivation therapy, ADT).
What is the basis for this approval?
Apalutamide was approved based on the results of the SPARTAN trial, which was a randomized, double-blind, placebo-controlled, phase III trial. A total of 1,207 men with NM-CRPC and a prostate-specific antigen (PSA) doubling time of 10 months or less were enrolled in the trial and randomized in a 2:1 fashion to apalutamide 240 mg daily in combination with ADT or placebo with ADT until first detection of distant metastasis. Patients were stratified upon PSA doubling time (> 6 months or <= 6 months), use of bone-sparing agents, and classification of nodal disease.
The primary endpoint was metastasis-free survival. At the point of the planned analysis, the median metastasis-free survival was 40.5 months in the apalutamide group compared to 16.2 months in the placebo group (HR=0.28, p<0.001). Additionally, the secondary endpoint of median progression-free survival was longer with apalutamide than with placebo (HR=0.29, p<0.001) (N Engl J Med 2018;378:1408-1418).
How do you administer this drug?
Apalutamide is administered as four 60 mg tablets for a total daily dose of 240 mg orally daily. It can be given with or without food.
Are there any premedications needed for apalutamide?
There are no required premedications for apalutamide.
What are the common side effects associated with apalutamide (> or =10%)?
* Hematologic: anemia, leukopenia, lymphocytopenia
* Cardiovascular: hypertension, peripheral edema
* GI: diarrhea, nausea, decreased appetite
* General: fatigue, falling
* Dermatologic: skin rash
* Endocrine & Metabolic: hypercholesterolemia, hyperglycemia, hypertriglyceridemia, hyperkalemia, hot flashes
* Neuromuscular & Skeletal: arthralgia, bone fracture
What are the uncommon side effects associated with apalutamide (less than 10%)?
Additional side effects include ischemic heart disease (4%), cardiac failure (2%), pruritus (6%), and hypothyroidism (8%). Less than 1 percent of patients postmarketing exhibited seizures while receiving apalutamide.
Are there any important drug interactions I should be aware of?
Apalutamide is a substrate of CYP2C8 and CYP3A4 and has been found to strongly induce CYP3A4 and CYP2C19. Caution should be taken when administering apalutamide with other medications known to be a substrate of CYP3A4 and CYP2C19 and have a narrow therapeutic index.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no known renal or hepatic dose adjustments for apalutamide; however, it has not been studied in severe renal or hepatic dysfunction.
Practical tips
* If a patient is started on new medications, it is recommended to evaluate for drug-drug interactions as apalutamide has significant drug interactions. Avoid concomitant use of CYP3A4 substrates, such as verapamil, diltiazem, and substrates of CYP2C19, such as warfarin and phenytoin.
* If a dose reduction is needed for apalutamide, it should be done in 60 mg increments. Since apalutamide is supplied in 60 mg capsules, the dose reduction will be a reduction in the number of daily capsules the patient takes.
What should my patients know about apalutamide?
Patients should contact their health care provider if they experience any of the following:
* Seizures
* Falling
* Fractures
What else should I know about apalutamide?
* Males with reproductive potential should be educated on use of effective contraception. Apalutamide is contraindicated in pregnancy.
* Monitor and manage risk for fractures and falls using established treatment guidelines and consider use of appropriate bone targeted therapies. Consider assessing bone mineral density testing at baseline prior to therapy and every 6 months thereafter.
What useful links are available regarding apalutamide?
* http://www.janssenlabels.com/package-insert/product-monograph/prescribing-inform
* https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm596796.htm
Any ongoing clinical trials related to apalutamide?
Clinical trials with apalutamide are being conducted to investigate the place in therapy for the treatment of prostate cancer. Apalutamide is being evaluated in combination with abiraterone as neoadjuvant treatment prior to prostatectomy and in combination with docetaxel. More information is available about the clinical trials at https://clinicaltrials.gov.
JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor.